Calcineurin is a calcium-dependent, serine/threonine phosphatase that is a signal transduction mediator involved in a variety of pathways including T cells. There are 3 isoforms of the catalytic subunit of calcineurin—α, β, and γ—and our work and that from other laboratories have identified unique and distinct roles for the α and β isoforms. Importantly, the β isoform appears to be the primary isoform required for normal activity of T cells.
The addition of calcineurin inhibitors (cyclosporin A and FK506) (calcineurin inhibitors) to immunosuppressive regiments reduces the incidence of acute allograft rejection and effectively doubles one-year survival of kidney transplant patients. However, long-term graft survival has improved far less significantly, with only 66% and 78% of deceased donor and living donor recipients, respectively, surviving 5 years. This statistic is even more striking when considered for different racial groups. 80% of Caucasians who receive living donor organs survive for 5 years while only 64% of African Americans live that long. Similar trends are observed for recipients of deceased donor organs; there is a 70% survival rate for Caucasians and only 55% for African Americans. Understanding mechanisms that contribute to disparate outcomes for transplant patients is an area of tremendous importance. Despite considerable effort, no consensus on the underlying causes has been reached that adequately explains racial disparities in long-term outcomes.
Cyclosporin A (CsA) and FK506 exert their immunosuppressive action by inhibition of the calcium-dependent phosphatase calcineurin. Calcineurin is known to be activated downstream of the T cell receptor and regulates transcription factors including the Nuclear Factor of Activated T cells (NFATs). NFATc proteins, in turn, control expression of cytokines including IL-2 and IL-4. Blockade of calcineurin/NFAT activity inhibits T cell activity and results in immune suppression. Although CsA has been clinically used for more than 20 years and FK506 over a decade, target blood levels for maintenance immunosuppression have yet to be properly defined. Therapeutic monitoring of trough CI concentration has proven to be a poor clinical indicator as some patients experience rejection in the presence of adequate or even high blood CI concentrations, whereas others develop toxicity even when blood trough concentrations are low. Discrepancies between CI dose and clinical immune suppression suggest that calcineurin activity itself may be a source of variability. However, there have been only limited studies that directly measure calcineurin activity, and there is no data regarding factors which may affect the calcineurin sensitivity to inhibition by cyclosporin and FK506.